The effect of previous treatment with bisphosphonate and renal impairment on the response to denosumab in osteoporosis: a 'real-life' study.

PURPOSE: To investigate changes in bone mineral density (BMD) following denosumab after previous bisphosphonate therapy and the impact of chronic kidney disease (CKD) on response. METHODS: A retrospective study of 134 patients (11 M, 123 F) aged [mean (SD)] 72 [11] years on denosumab was undertaken. Ninety-five patients had previously been on oral and 28 on iv bisphosphonate. Lumbar spine (LS), total hip (TH) and femoral neck (FN) BMD were measured before treatment and at 2.7 [1.2] years. GFR was < 35 ml/min in 24 patients (18%). Ninety-four (18 M, 76 F) patients aged 71 [11] years transitioning to zoledronate were also studied. RESULTS: BMD improved following denosumab [mean (SEM) % change LS: 6.0 (0.62) p < 0.001, TH: 2.28 (0.64) p < 0.001, FN: 1.9 (0.77) p = 0.045]. Changes at the TH and FN were lower in patients with GFR < 35 ml/min (Group B) compared to those with GFR > 35 ml/min (Group A) [% change TH; Group A: 2.9 (0.72), Group B: - 0.84 (1.28), p = 0.015, FN; Group A: 2.76 (0.86), Group B: - 1.47 (1.53), p = 0.025]. % change in BMD at the FN and PTH were negatively associated (r = - 0.25, p = 0.013). BMD changes were not different at 12-18 months between patients on denosumab compared to zoledronate [% change at LS: denosumab: 3.97% (0.85), zoledronate: 2.6% (0.5), p = 0.19 TH: denosumab: 0.97% (0.58), zoledronate: 0.92% (0.6), p = 0.95). CONCLUSION: Denosumab increases BMD following previous bisphosphonate treatment and is comparable to zoledronate. Lower response seen at the hip in CKD is related to PTH concentrations.

Florid diabetic retinopathy and its response to treatment by photocoagulation or pituitary ablation.

A group of 34 patients with florid diabetic retinopathy are reported. Nine of these had at least one eye untreated and of these only two maintained vision at one year-the others were blind. Ten patients had 11 florid eyes treated by photocoagulation. At one year six were blind and five had good vision. At two years only three could still see. Of 20 pituitary-ablated patients with 29 florid eyes, only three were blind at one year. Even at five years, 12 of 17 eyes could see and only two patients were blind. The one- and two-year visual acuities were significantly better in the pituitary ablated eyes than in the untreated and photocoagulated ones (p = 0.01-0.03). It is suggested that for this rare form of retinopathy pituitary ablation remains the treatment of choice if vision is to be maintained.

Low serum osteocalcin levels in glucocorticoid-treated asthmatics.

Serum osteocalcin (OC) levels were measured in 19 asthmatic patients receiving long term glucocorticoid therapy and in age- and sex-matched asthmatic patients not receiving this treatment. In the glucocorticoid-treated patients, the mean OC level was approximately 50% less than that in the control group (P less than 0.001), and there was a direct correlation between serum OC and 1,25-dihydroxyvitamin D [1,25-(OH)2D; r = 0.71; P less than 0.001]. Multiple regression analysis in a total of 39 glucocorticoid-treated patients indicated that OC correlated directly to 1,25-(OH)2D and inversely to glucocorticoid dose. There was no correlation between OC and 1,25-(OH)2D in the control group and no significant difference in mean serum 1,25-(OH)2D between the steroid-treated asthmatic patients and the asthmatic control patients. The effect of a 4-day course of oral 1,25-(OH)2D on serum OC was studied in six patients with glucocorticoid excess and six normal subjects. There was a similar percent increase in OC levels in both groups, though the basal concentrations and absolute increases were substantially less in the steroid-treated group. It is likely that the depression of serum OC in glucocorticoid-treated patients results from the reduction in the rate of bone formation induced by these hormones.

Gel filtration of human urinary immunoreactive luteinizing hormone.

In human urinary concentrates and also in a urinary gonadotrophin standard (2nd IRP-HMG), gel-filtration analysis revealed three main peaks of immunoassayable luteinizing hormone (LH). A similar analysis of LH extracted from human pituitaries showed most of the activity in a peak of larger molecular weight, and only minor fractions in the positions of the urinary peaks. In an extract of normal human serum, analyss showed only one similar peak of large molecular weight, which also emerged before the urinary peaks. During an i.v. infusion of pituitary LH into normal men, the urinary LH activity increased but was still found only in the same three peaks on gel filtration, and all were of a molecular weight smaller than that of the infused material; but a higher proportion of the urinary LH was found in the earliest of these peaks compared with that found before infusion. Conversely, 20-35 h after the i.v. infusion, there was a slightly higher proportion of LH activity in the third peak of smallest molecular weight. These findings suggest that the urinary immunoassayable LH, which is found in three peaks of different molecular weights, is derived from the pituitary or serum LH of higher molecular weight. The changes in the proportions of larger or smaller molecular weight fractions in the urine during and after LH infusion suggest that the earliest peak may be disaggregated serum LH, while the last or smallest molecular weight peak may comprise metabolites of LH.

Production and storage of (125-I) thyroxine and (125-I) triiodothyronine of high specific activity.

High specific activity [125-I] triiodothyronine and [125-I] thyroxine have been produced regularly by the chloramine T radioiodination method. Simultaneous production of [125-I] triiodothyronine and [125-I] thyroxine is usual when diiodothyronine or triiodothyronine are employed as the starting materials. Specific activities reached vary with the starting compound (diiodothyronine, triiodothyronine, thyroxine) used, as both substitution and, less readily, exchange of iodine atoms take place. Starting with diiodothyronine specific activities of approximately 2400 and 5200 Ci/g were achieved for [125-I]triidothyronine and [125I] thyroxine, respectively, and, similarly, specific activities of approximately 1200 and 4000 Ci/g for [125I] triiodothyronine and [125I]-thyroxine, respectively, were reached when triiodothyronine was the starting material. [125-I] Triiodoacetic acid and [125I] tetraiodoacetic acid have been produced in the same way from triiodoacetic acid. By column chromatography on Sephadex G-25 (fine), eluting with alkaline phosphate buffer, good separation of the radioiodinated products has been readily achieved. Studies on the stability of the radioiodinated hormones showed that 50% methanol, ethanol, propanol and propylene glycol were all equivalent as preserving agents and, further, that the stability of the radioiodinated hormones was linearly related to the concentration of these preserving agents.

Radiological assessment of Paget's disease of bone after treatment with the bisphosphonates EHDP and APD.

The effects of therapy on the osteolytic bone lesions of Paget's disease have been assessed from serial bone radiographs. Changes in the rate of progression of lytic "wedge" lesions were measured and alterations in the texture of lytic "blade" lesions were graded on an empirical scale. Useful matching was possible using standard radiographs, although special care was needed to avoid artefacts from suboptimal positioning, magnification and variation in exposure. Serial radiographs were obtained of 57 lytic blade lesions in 54 patients receiving treatment with the bisphosphonate 1-hydroxyethylidene-1, 1-bisphosphonate (EHDP) and of 20 lesions in 20 patients treated with oral or intravenous 3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (APD). Treatment with EHDP was associated with a significant deterioration in bone texture in 50% of lytic blade lesions, and with healing in only 20%. Deterioration was accompanied by an increase in local bone pain in 17% of these patients. In contrast, significant healing was observed in 17 of 20 lytic lesions (eight wedge, nine blade) within 6 months of beginning a course of intravenous or oral APD. In four of eight patients the progression of a lytic tibial wedge was arrested and in the remaining four the direction of wedge movement was reversed. In two patients the wedge had almost completely "filled in", making measurement difficult. Bone healing was usually accompanied by pain relief, reduction in skin temperature and rapid suppression of the urine hydroxyproline (uHP) into the normal range. However, in four patients who received intravenous APD, repair of lytic bone lesions was observed despite persisting elevation of uHP. These improvements with APD were sustained at 12 months, although in one patient whose biochemical indices were restored to normal the resorption front showed further progression, despite initial temporary reversal. The trends apparent in these short-term studies were also seen in four patients in whom wedge velocities were measured over periods of 6-10 years. These results confirm that after treatment of Paget's disease, bone healing or deterioration can be accurately assessed from serial standard radiographs. Reproducible matching is best achieved by ensuring that all radiographs are taken by the same radiographer. Minor alterations in radiological bone texture provide an important index of drug effect which is not always apparent from measurement of biochemical and other indices.

The response to treatment with pituitary growth hormone: the New Zealand experience.

Ninety-four growth hormone deficient New Zealand children were treated with thrice weekly intramuscular injections of human pituitary growth hormone (GH) from 1979 to 1985 and the results from 43 children were analysed in detail. Their height velocity was mean (SD) 4.0 (1.9) cm/yr immediately prior to treatment and 8.5 (3.1) cm/yr in the first year of treatment. In each of the first three years of treatment the height velocity was significantly increased (p less than 0.001), but there was a significant decline in height velocity between the first and second, and second and third years. Nevertheless each year of treatment gave a highly significant gain in relative height. Bone age did not advance more rapidly than chronological age during the first two years of treatment, but did so subsequently. The response to GH, as assessed by the increase in relative height, was negatively correlated with the relative height at the start of treatment and with the maximum pretreatment plasma GH response to insulin hypoglycaemia. There was no correlation with pretreatment relative height velocity or aetiology of GH deficiency. Height velocity improved in five of 14 children treated with thyroxine after starting GH. Discontinuation of GH for one year in 34 children resulted in a highly significant reduction in growth rate from 7.5 (2.4) cm/yr to 2.5 (2.0) cm/yr, however four prepubertal children continued to grow at a rate exceeding 4 cm/yr.